当实验室工艺在放大生产后出现意外的杂质，问题根源可能并非工艺本身，而是工厂的海拔高度，本文将通过Takeda公司的一个真实案例，揭示高海拔环境如何通过影响溶剂沸点与反应器操作，进而引发杂质与残留金属含量超标的关键细节。具体内容如下：
From Lab to Plant: Managing Operational Environment During Scale-Up
从实验室到工厂：放大生产过程中管理操作环境
Scale-up comes with its challenges, with adaptations to the process, materials and equipment often anticipated. Though these challenges can result from equipment, raw material differences, and process variability, operational environments must be a major focus during lab trials, as Yuhei Yamamoto and his team at Takeda learned in a recent experience.
工艺放大过程会伴随诸多挑战，通常需要对工艺、物料和设备进行调整。尽管这些挑战可能由设备问题、原辅料差异及工艺变异性导致，但操作环境必须成为实验室试验期间的重点关注对象，正如 Yuhei Yamamoto 及其在 Takeda 的团队在近期一次实践中所认识到的那样。
Yamamoto and his lab team took their Suzuki-Miyaura coupling reaction to new heights (literally), and published the lessons they learned from their scale-up with a contract manufacturing organization (CMO) at a higher altitude. CMOs at higher elevations are certainly not the norm; however, the research can help those with palladium-catalyzed reactions recognize early considerations and avoid unforeseen complications during scale-up.
Yamamoto 及其实验室团队将其铃木 - 宫浦偶联反应（Suzuki-Miyaura coupling reaction）提升到了新的高度 —— 而且是从字面意义上来说。他们与一家位于更高海拔的合同生产组织（contract manufacturing organization, CMO）合作进行工艺放大，并将从中吸取的经验教训整理发表。高海拔地区的 CMO 当然并非普遍情况；不过，这项研究可为从事钯催化反应（palladium-catalyzed reactions）的研究者提供帮助，助力他们识别工艺放大前期需考虑的因素，避免过程中出现不可预见的问题。
Troubleshooting Cause and Solutions
故障原因与解决方案
Palladium is sensitive to temperature and oxygen. To maintain the internal conditions of the reaction, the CMO (at a higher altitude) needed to use a pressure reactor.
钯对温度和氧气敏感。为了维持反应的内部条件，位于高海拔地区的合同生产组织（CMO）需要使用加压反应器。
“Reaction temperature was an important factor and needed to be maintained at 85–95 °C. At high altitude, the solvent refluxed at 80 °C, and the reaction would not go to completion at this temperature. The CMO used a reactor that could be pressurized, allowing the internal temperature to reach 85–95 °C,” explained Yamamoto.
反应温度是一个重要因素，需要维持在 85–95°C。在高海拔地区，溶剂在 80°C 时回流，而在此温度下反应无法进行完全。合同生产组织使用了可加压的反应器，使内部温度能够达到 85–95°C 。
The researchers established solid reaction conditions in their lab; however, when the CMO performed the reaction at a higher altitude using the pressure reactor, the crystals had elevated levels of palladium. “The release test of the compound included impurity levels and residual palladium, and this was identified by checking the master batch record and comparing it to the laboratory procedure and data to identify any differences,” added Yamamoto.
研究人员在实验室中确定了可靠的反应条件；然而，当合同生产组织在高海拔地区使用加压反应器进行反应时，晶体中的钯含量升高了。该化合物的放行测试包括杂质水平和残留钯含量，这是通过检查主批记录并将其与实验室流程和数据进行比较以识别任何差异来确定的。
Impurities are not uncommon with Suzuki-Miyaura coupling, according to Yamamoto. Dehalogenation, homo-coupling and oxidation can all produce impurities, but the out-of-expectation (OOE) levels of related substances led to concern. “Many parameters can affect impurity formation. If we consider which conditions cause impurity issues during scale-up, they include the presence of air (or oxygen), mixing efficiency, nitrogen flow, heating efficiency, and reaction temperature,” explained Yamamoto.
据Yamamoto介绍，铃木 - 宫浦偶联反应中出现杂质并不罕见。脱卤、自身偶联和氧化都可能产生杂质，但相关物质的超出预期（OOE）水平引发了担忧。许多参数都会影响杂质的形成。如果我们考虑在放大生产过程中哪些条件会导致杂质问题，这些条件包括空气（或氧气）的存在、混合效率、氮气流、加热效率和反应温度。
His team investigated stirring efficiency, jacket temperature, reaction pressure and presence/absence of oxygen to determine the cause of the excess palladium.
他的团队调查了搅拌效率、夹套温度、反应压力以及氧气的存在与否，以确定钯过量的原因。
The research team deduced that the elevated impurities from the reaction were caused by a high external temperature. They found that there were local hot spots near the high-temperature jacket.
研究团队推断，反应中杂质升高是由较高的外部温度引起的。他们发现高温夹套附近存在局部热点。
To tackle the crystal quality, the scientists noted that the jacket temperature needed to be below 105 °C. This measure helped to reduce impurities from the reaction. However, the strict aerobic conditions prevented them from removing the palladium after the reaction, and they needed to add air.
为了解决晶体质量问题，科学家们指出夹套温度需要低于 105°C。这一措施有助于减少反应产生的杂质。然而，严格的需氧条件使他们无法在反应后去除钯，因此他们需要通入空气。
Since adding air directly was not advisable, the team added air via O₂/N₂ bubbling. This was integrated after the reaction to facilitate palladium removal and enhance crystal quality.
由于直接通入空气不可取，团队通过 O₂/N₂鼓泡的方式通入空气。这一步骤在反应后进行，以促进钯的去除并提高晶体质量。
Lessons Learned
经验教训
In their research, the scientists emphasized the importance of mimicking the equipment and environments to be used for manufacturing. In this case, having utilized the pressure reactor in the process would have highlighted impurities that led to earlier process refinement.
在他们的研究中，科学家们强调了模拟生产中将要使用的设备和环境的重要性。在这种情况下，如果在过程中使用了加压反应器，就会更早地发现杂质，从而更早地对工艺进行优化。
Yamamoto continued that other reactions at high altitude should take heed. “This issue is not limited to the S-M reaction and can occur with any reaction if the decrease in boiling point at high altitude is not considered. Therefore, it is recommended that, when running reactions at reflux or high temperature, a pressure reactor should be used in the lab and relevant data should be collected,” he furthered. Altitude is not a concern for reactions that do not require high temperatures or reflux.
Yamamoto继续表示，高海拔地区的其他反应也应引起注意。“这个问题不仅限于铃木 - 宫浦反应，如果不考虑高海拔地区沸点的降低，任何反应都可能出现这种情况。因此，建议在进行回流或高温反应时，实验室应使用加压反应器并收集相关数据，” 他进一步说道。对于不需要高温或回流的反应，海拔高度不是问题。
Good communication is the key, according to Yamamoto, concluding, “For manufacturers at high altitude, I recommend maintaining good communication with laboratory chemists, especially if the lab chemists are located at normal altitude.”
Yamamoto总结道，良好的沟通是关键：“对于高海拔地区的制造商，我建议与实验室化学家保持良好的沟通，尤其是当实验室化学家位于正常海拔地区时。”
